Antiviral
PREGNANCY RECOMMENDATION: Limited Human Data—Animal Data Suggest Low Risk
BREASTFEEDING RECOMMENDATION: No Human Data—Potential Toxicity
PREGNANCY SUMMARY
The human pregnancy experience with telbivudine is very limited. Although the animal reproduction data are encouraging, additional human pregnancy experience is required for a full assessment of the embryo–fetal risk. Theoretically, exposure to agents in this class at the time of implantation could impair fertility as a result of embryonic cytotoxicity. This toxicity was not observed with telbivudine in animal studies but has not been studied in humans. Mitochondrial dysfunction has been reported with two nucleoside reverse transcriptase inhibitors (see Lamivudine and Zidovudine). However, no appreciable mitochondrial toxicity was observed with telbivudine at concentrations much higher than those required to inhibit hepatitis B viral DNA synthesis (1). If indicated, the drug should not be withheld because of pregnancy. Physicians are encouraged to register exposed patients in the Antiretroviral Pregnancy Registry by calling 1-800-258-4263 (1).
FETAL RISK SUMMARY
Telbivudine is an oral synthetic thymidine nucleoside analog with antiviral activity against hepatitis B virus DNA polymerase. It has no activity against the HIV. It is phosphorylated to the active metabolite by cellular kinases. Telbivudine is indicated for the treatment of chronic hepatitis B in adult patients with evidence of viral replication and either evidence of persistent elevations in serum aminotransferases (alanine aminotransferase [ALT] or aspartate aminotransferase [AST]) or histologically active disease. The agent is in the same class of nucleoside reverse transcriptase inhibitors as abacavir, didanosine, emtricitabine, lamivudine, stavudine, tenofovir, and zidovudine. Plasma protein binding is very low (3%). The plasma terminal elimination half-life is 40–49 hours and the drug is eliminated primarily by urinary excretion of unchanged drug (1).
Reproduction studies have been conducted in rats and rabbits. No evidence of fetal harm was observed in these species at exposures up to 6 and 37 times, respectively, the exposure levels from the human therapeutic dose of 600 mg/day (HTD). The drug crossed the placentas of both species (1).
Studies with telbivudine have found no evidence of carcinogenicity in mice and rats or genotoxicity in multiple assays (1,2). No evidence of impaired fertility was seen in male and female rats given doses that produced systemic exposures about 14 times the HTD (1).
It is not known if telbivudine crosses the human placenta. The low molecular weight (about 242) and plasma protein binding, and long elimination half-life suggest that the drug will reach the embryo and fetus.
The Antiretroviral Pregnancy Registry reported, for the period January 1989 through July 2009, prospective data (reported before the outcomes were known) involving 4702 live births that had been exposed during the 1st trimester to one or more antiretroviral agents (3). Congenital defects were noted in 134, a prevalence of 2.8% (95% confidence interval [CI] 2.4–3.4). In the 6100 live births with earliest exposure in the 2nd/3rd trimesters, there were 153 infants with defects (prevalence 2.5%, 95% CI 2.1–2.9). The prevalence rates for the two periods did not differ significantly. There were 288 infants with birth defects among 10,803 live births with exposure anytime during pregnancy (prevalence 2.7%, 95% CI 2.4–3.0). The prevalence rate did not differ significantly from the rate expected in a nonexposed population. There were six outcomes exposed to telbivudine (five in the 1st trimester and one in the 2nd/3rd trimesters) in combination with other antiretroviral agents. There were no birth defects. In reviewing the birth defects of prospective and retrospective (pregnancies reported after the outcomes were known) registered cases, the Registry concluded that, except for isolated cases of neural tube defects with efavirenz exposure in retrospective reports, there was no other pattern of anomalies (isolated or syndromic) (3) (see Lamivudine for required statement).
BREASTFEEDING SUMMARY
No reports describing the use of telbivudine during human lactation have been located. The molecular weight (about 242), plasma protein binding (3%), and long elimination half-life (40–49 hours) suggest that the drug will be excreted into breast milk. The effect of this exposure on a nursing infant is unknown. Infants of mothers with hepatitis B are at high risk of chronic hepatitis B virus infection when the maternal infection occurs perinatally or in early infancy (4). Hepatitis B immune globulin and hepatitis B virus vaccine given simultaneously to the infant at birth will prevent chronic infection in nearly all cases, regardless of whether the infant is breastfed (4). If the mother elects to breastfeed, the infant should be monitored closely for the most common telbivudine-induced toxicities observed in adults, such as upper respiratory infection, fatigue, malaise, abdominal pain, cough, fever, insomnia, rash, nausea, vomiting, diarrhea, and loose stools.
References
1.Product information. Tyzeka. Novartis Pharmaceuticals, 2007.
2.Bridges EG, Selden JR, Luo S. Nonclinical safety profile of telbivudine, a novel potent antiviral agent for treatment of hepatitis B. Antimicrob Agents Chemother 2008;52:2521–8.
3.Antiretroviral Pregnancy Registry Steering Committee. Antiretroviral Pregnancy Registry International Interim Report for 1 January 1989 through 31 July 2009. Wilmington, NC: Registry Coordinating Center; 2009. Available at www.apregistry.com. Accessed May 29, 2010.
4.Lawrence RM, Lawrence RA. The breast and the physiology of lactation. In: Creasy RK, Resnik R. eds. Maternal and Fetal Medicine. 5th ed. Philadelphia, PA: WB Saunders, 2004:146, 148.